Multicellular organisms must maintain a complex pattern of gene expression, regulating genes differently based on cell type and developmental stage, for healthy growth. Understanding the mechanisms of regulation of gene expression is an important step in understanding the pathogenesis of diseases such as cancer, which generally involves large-scale misexpression of cellular genes. One model for studying the control of gene expression is mammalian X-chromosome inactivation. One copy of the X chromosome in the cells of female mammals is transcriptionally silenced to compensate for the presence of two X chromosomes in female cells versus one in male cells. While most genes on the inactive X chromosome (Xi) are not expressed, some genes escape inactivation. Genes that escape inactivation display euchromatic patterns of his tone modification, the inverse of the pattern seen through most of the heterochromatic Xi. On the human Xi, genes escaping inactivation tend to form clusters, suggesting that escape is regulated at the level of chromatin domains rather than single genes. The goals of this project are twofold. First, the cis-regulatory elements that allow genes to escape X-chromosome inactivation in mice will be identified. Once this is accomplished, the trans-acting factors that mediate the activity of these elements will be identified.